Disrupted RGS coupling underlies a clinically distinct subset of GNAO1-related disorder

Heterotrimeric G proteins are transducers for a wide variety of neurotransmitter receptors. Mutations in the G protein αo subunit are implicated in an early-onset neurological condition, GNAO1-related disorder, that manifests as movement disorders, developmental delays, and/or epileptic seizures. In a screen of disease-linked mutations in Gαo, we identified a subset that had no obvious biochemical defects, warranting further investigation. By structural modeling, protein-protein binding experiments in vitro and in cells, as well as measures of downstream ion channel electrophysiology, we identified a subset that impairs interactions with regulator of G protein signaling (RGS) proteins. RGS proteins accelerate G protein GTPase activity and are therefore critical for proper neurotransmitter signaling. Further, synthesis of current clinical data revealed that patients harboring these variants have comparatively mild symptoms. Our study demonstrates the importance of RGS regulation in G protein function, cell signaling, and human neurobiology.